RP3 in Combination With 1L or 2L Therapy in Patients With Locally Advanced Unresectable or Metastatic HCC

Recurrent Hepatocellular Carcinoma Clinical Trial

Official title:

A Phase 2, Open-label, Multicenter Study Investigating RP3 Oncolytic Immunotherapy in Combination With First- or Second-line Therapy in Patients With Locally Advanced Unresectable or Metastatic Hepatocellular Carcinoma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05733598
• Other study ID #: RP3-003
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 1, 2024
• Est. completion date: July 1, 2027

Study information

• Verified date: December 2023
• Source: Replimune Inc.
• Contact: Clinical Trials at Replimune
• Phone: 1-781-222-9570
• Email: Clinicaltrials[@]replimune.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 2, open-label, 2-cohort clinical study evaluating RP3 in combination with atezolizumab plus bevacizumab as First- or Second-line Systemic Therapy in patients with locoregionally advanced and/or metastatic Hepatocellular Carcinoma not amenable to surgical resection or standard locoregionally directed therapies.

Description:

RP3 is a genetically modified herpes simplex type 1 virus (HSV-1) that expresses exogenous genes (anti-CTLA-4 antibody, CD40 ligand and h4-1BBL) designed to directly kill tumor cells and generate a systemic anti-tumor immune response

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: July 1, 2027
• Est. primary completion date: April 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female =18 years of age.

2. Has locoregionally advanced unresectable, recurrent, and/or metastatic HCC, with the diagnosis confirmed by histologic or cytologic analysis or clinical features plus imaging criteria (using LI-RADS v2018) according to the American Association for the Study of Liver Diseases criteria for patients with cirrhosis.

3. Child-Pugh A, as determined within 14 days before first study treatment.

4. Has at least 1 measurable tumor of =1cm in longest diameter (or =1.5cm shortest diameter for lymph nodes)as defined by RECIST 1.1.

5. Has injectable tumor(s), which alone or in aggregate, total at least 1cm in diameter.

6. Must be willing to consent to provide fresh tumor biopsy sample or archival tumor biopsy sample obtained within 60 days before initiation of study treatment.

7. Has adequate hematologic function, including:

• White blood cell (WBC) count =2.0 × 109/L

• Absolute neutrophil count (ANC) =1.5 × 109/L(without granulocyte-colony stimulating factor support)

• Platelet count =50× 109/L(without transfusion)

• Hemoglobin =8.5 g/dL (may have received transfusions; however, patient must not be transfusion-dependent).

8. Has adequate hepatic function including:

• Total bilirubin =3.0× upper limit of normal (ULN)

• Aspartate aminotransferase (AST) alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =5.0 × ULN.

9. Has adequate renal function, defined as serum creatinine =1.5 × ULN or creatinine clearance =30 mL/minute(measured using Cockcroft-Gault formula).

10. Serum albumin =2.8 g/dL.

11. Prothrombin time (PT) =1.5 × ULN (or international normalization ratio [INR] =1.7) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =1.5 × ULN.

Note: Patients who are on a stable dose of long-term coumadin therapy may be enrolled if the target INR is=2.5, provided that the INR can be safely reversed to=1.7 temporarily around the time of RP3 injection.

12. Eastern Cooperative Oncology Group (ECOG)performance status 0 or 1.

13. Female and male patients of reproductive potential must agree to avoid becoming pregnant or impregnating a partner and adhere to highly effective contraception requirements during the treatment period and for at least (a) 90 days after the last dose of RP3 or (b) 5 months after the last dose of atezolizumab or (c) 6 months after the last dose of bevacizumab, whichever is longer.

14. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (ß-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG within 72 hours before the first dose and a negative urine pregnancy test on Dose1 Day1.

15. Capable of giving signed informed consent which includes willingness to comply with the requirements and restrictions listed in the informed consent form and in this protocol.

1L Cohort only:

16. Patient is eligible for 1L systemic therapy with atezolizumab and bevacizumab Note:

Patients who have received prior local therapy (eg, radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization) are eligible provided the target lesion(s) have not been previously treated with local therapy or have subsequently progressed in accordance with RECIST 1.1.

2L Cohort only:

17. Must have progressed on or after 1 systemic therapy, which must have included anti-PD-1 or anti-PD-L1therapy (eg, atezolizumab plus bevacizumab combination, durvalumab plus tremelimumab combination, durvalumab, pembrolizumab, or nivolumab monotherapy or nivolumab plus ipilimumab or lenvatinib plus pembrolizumab combination) as their immediate prior treatment regimen.

Exclusion Criteria:

1. Child-Pugh B or C.

2. Patients with untreated or incompletely treated esophageal and/or gastric varices with active/recent bleeding or at high-risk for bleeding.

Note: All patients must undergo an esophagogastroduodenoscopy, and all varices (irrespective of size) must be assessed and treated per local standards of care before enrollment. Patients who have undergone endoscopic management of all known varices with 120 days before initiation of study treatment do not need to repeat the procedure.

3. Significant bleeding event within the last 12 months that places the patient at unjustifiable risk for bleeding from intratumoral injection procedures, based on Investigator or interventional radiologist assessment.

4. Macroscopic intravascular invasion into the hepatic and/or segmental portal vein(s), main or segmental hepatic veins and/or ateries, inferior vena cava, and/or other major blood vessel, or into the hepatic and/or common bile duct(s)

5. Histologic evidence of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma with HCC, or other rare histologic HCC variants.

6. History of medically refractory hepatic encephalopathy and/or hepato-renal syndrome.

7. Disease that is amenable to surgical and/or standard locoregionally directed therapies.

8. Presence of liver tumors that are estimated to invade more than one-third of the liver.

9. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring drainage within 7days before enrollment.

10. Known acute or chronic hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known acute or chronic hepatitis C virus (defined as HCV RNA [qualitative] is detected).

Note: Patients who have been effectively treated are eligible for enrollment. Patients must be negative for HBsAg and HCV RNA

11. Known human immunodeficiency virus (HIV) infection.

Note: Testing for HIV is not required unless mandated by local health authority or clinically indicated.

12. Active significant herpetic infections or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis) or requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).

Note: Patients with sporadic cold sores may be enrolled if no active cold sores are present at the time of Dose1 Day 1.

13. Systemic infection requiring IV antibiotics or other serious infection within 14days before initiating study therapy.

14. Received a live vaccine within 28 days before the first dose of study treatment.

15. Central nervous system (CNS) metastases and/or carcinomatous meningitis.

16. Prior malignancy, other than HCC, active within the previous 3 years, except for localized cancers that have apparently been cured including basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

17. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment. Note: Patients who have entered the follow-up phase of an investigational study may participate if it has been more than 4 weeks after the last dose of the previous investigational agent.

18. Systemic anticancer therapies within 4 weeks of the first dose of study drug. The prior anti-PD-1 or anti-PD-L1 containing regimen is excluded from this requirement for the 2Lcohort.

Note: Patients must have recovered (to Grade =1 or baseline) from all AEs due to previous therapies. Patients with Grade =2 neuropathy may be eligible if approved by the Medical Monitor.

19. Received radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities (except for radiation-induced xerostomia), not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.

20. Received prior treatment with an oncolytic virus therapy.

21. History of significant cardiac disease including myocarditis or congestive heart failure (defined as New York Heart Association Functional Classification III or IV), or unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction within 6 months of enrollment.

22. Uncontrolled infection.

23. History of interstitial lung disease, idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), non-infectious pneumonitis that required steroids, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

Note: History of radiation pneumonitis in a prior radiation field (radiation fibrosis) is permitted.

24. Active tuberculosis.

25. History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the Investigator or the Medical Monitor, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion.

26. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the Investigator.

27. Active, known, or suspected autoimmune disease requiring systemic treatment. Note:

Patients with type 1 diabetes mellitus and/or hypothyroidism requiring only hormone replacement, and/or with autoimmune skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, and/or prior non-serious autoimmune conditions not expected to recur are permitted to enroll.

28. Conditions requiring treatment with immunosuppressive doses (>10 mg per day of prednisone or equivalent) of systemic corticosteroids within 14 days before Dose1 Day

1. Note: Patients who require a brief course (=7 days) of corticosteroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded. Physiologic replacement doses of systemic corticosteroids are permitted, only if the dose does not exceed 10 mg/day prednisone equivalent.

29. History of allergy or sensitivity to study drug components or prior monoclonal antibody treatment; known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation.

30. History of allergy or sensitivity to study drug components or prior monoclonal antibody treatment; known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation. \History of life-threatening toxicity related to prior immune therapy (eg, anti-cytotoxic T lymphocyte antigen 4 or anti-PD-1/anti-PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways [eg, CD40, 4-1BB]) except those that are unlikely to recur or are expected to be manageable with standard countermeasures (eg, hormone replacement after adrenal crisis). Individual cases should be discussed with Medical Monitor as appropriate.

31. Conditions in which anticoagulant therapies cannot be safely stopped in the periprocedural period or patients on coumadin with a target INR >2.5 or that cannot be temporarily reversed toINR=1.7 around the time of intratumoral injections.

32. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2weeks before initiating study treatment.

33. Prior organ transplantation including allogeneic stem-cell transplantation.

34. Major surgery within 28days before starting bevacizumab or anticipated major surgery while on study.

Note: If a patient received major surgery, they must have recovered adequately from the intervention before starting study treatment and must have adequate wound healing, based on surgeon's assessment, before starting bevacizumab.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Locally Advanced Hepatocellular Carcinoma
• Metastatic Hepatocellular Carcinoma
• Recurrent Hepatocellular Carcinoma

Intervention

Biological:
• RP3
Genetically modified herpes simplex type 1 virus
• atezolizumab
anti-PD-L1 monoclonal antibody
• bevacizumab
anti-VEGF therapy

Locations

Country	Name	City	State
France	Hôpital BEAUJON	Clichy
France	Université Claude Bernard Lyon 1, Centre Hospitalier Lyon Sud	Lyon
France	CHU Bordeaux	Pessac
France	Centre Eugène MARQUIS	Rennes
France	Institute Gustave Roussy Paris	Villejuif
France	Service d'Ocologie Digestive et Medicale Hopital Paul Brousse	Villejuif
Germany	Krankenhaus Nordwest	Frankfurt
Germany	Uniklinikum Heidelberg National Center for Tumors Heidelberg (NCT)	Heidelberg
Germany	University Hospital Leipzig Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Pneumatology, Infectiology	Leipzig
Germany	Universitätsklinikum Mainz Hautklinik und Poliklinik	Mainz
Greece	"Hippocration" General Hospital of Athens, B' Department of Internal Medicine, Hepatogastroenterology Unit	Athens
Greece	University General Hospital of Herakleion	Heraklion
United Kingdom	Leeds Teaching Hospital NHS Trust / St James's University Hospital	Leeds
United Kingdom	Clatterbridge Cancer Center NHS Foundation Trust	Liverpool
United Kingdom	King's College Hospital	London
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	University of Cincinnati	Cincinnati	Ohio
United States	West Cancer Center	Germantown	Tennessee
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of California San Diego, UCSD	La Jolla	California
United States	University of Pennsylvania Abramson Cancer Center	Philadelphia	Pennsylvania
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	University of Washington Fred Hutchinson Cancer Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Replimune Inc.	Roche Pharma AG

Countries where clinical trial is conducted

United States,  France,  Germany,  Greece,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate per modified RECIST 1.1	Percentage of subjects achieving objective response (complete response + partial response)	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Frequency, Nature, and Severity of TEAEs and SAEs	Percentage of subjects with TEAEs and SAEs	From Screening through 60 days after last dose of RP3, or 135 days after last dose of atezolizumab/bevacizumab
Secondary	Overall Response Rate per RECIST modified for use in the HCC setting	Percentage of subjects with objective response (complete response + partial response) per RECIST modified for use in the HCC setting	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Duration of Response	Duration of response is defined as the time from documented response until the date of progression of disease, which was subsequently confirmed or with no further follow-up, or death due to any cause, whichever occurs first	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Duration of Clinical Benefit	Duration of clinical benefit is defined as the time from the first day of study treatment to last progression of disease, which was subsequently confirmed or with no further follow-up for response, or death due to any cause, whichever occurs first, for subjects who achieve complete response, partial response, or stable disease	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Complete response rate	Percentage of subjects achieving complete response	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Clinical Benefit Rate	Percentage of subjects achieving complete response, partial response, or stable disease	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Progression-free Survival	Progression-free survival is defined as the time from the first day of study treatment to the date of progression of disease, which was subsequently confirmed, or death by any cause, whichever occurs first	From Day 1 to documented progression of disease (up to 3 years)
Secondary	Overall Survival	Overall survival is defined as the time from the first day of study treatment to the date of death by any cause	From Day 1 to date of death by any cause (up to 3 years)